The effects of fasting for 12, 36 and 72 h were examined in 19 normal subjects. Each subject was studied before and during a euglycaemic (4 mmol/l) hyperinsulinaemic (100 m-units min-1 m-2) clamp. Measurements were made of palmitate turnover and oxidation, glucose disposal, thermogenesis, intermediary metabolites and cardiovascular variables. 2. Basal respiratory exchange ratio fell from 0.78 +/- 0.01 to 0.75 +/- 0.01 to 0.72 +/- 0.01 with fasting (P < 0.001). In response to the clamp it rose to 0.91 +/- 0.02, 0.83 +/- 0.01 and 0.77 +/- 0.01 after 12, 36 and 72h respectively. Metabolic rate rose during the clamp by 0.41 +/- 0.06, 0.11 +/- 0.03 and 0.14 +/- 0.04 kJ/min respectively (P < 0.001 for 36- and 72-h values versus that at 12h). 3. Fasting reduced total insulin-mediated glucose disposal rates from 42.6 +/- 2.5, to 31.0 +/- 1.8 to 21.3 +/- 1.5 mumol min-1 kg-1 body weight after 12, 36 and 72h respectively (P < 0.001). Glucose oxidation fell from 16.9 +/- 1.1 to 8.7 +/- 1.7 to 0.2 +/- 1.3 mumol min-1 kg-1 body weight over the same period (P < 0.001). Non-oxidative glucose disposal rates did not change significantly. 4. Basal plasma palmitate turnover increased with duration of fasting, being 1.16 +/- 0.08, 1.72 +/- 0.17 and 2.30 +/- 0.35 mumol min-1 kg-1 body weight. In response to the clamp, palmitate turnover fell to 0.42 +/- 0.05, 0.69 +/- 0.08 and 1.28 +/- 0.45 mumol min-1 kg-1 body weight. Plasma palmitate oxidation was 0.58 +/- 0.04, 0.75 +/- 0.06 and 1.13 +/- 0.11 mumol min-1 kg-1 body weight basally, and fell to 0.16 +/- 0.02, 0.28 +/- 0.04 and 0.43 +/- 0.13 mumol min-1 kg-1 body weight by the end of the clamp. The proportion of total lipid oxidation represented by plasma non-essential fatty acid oxidation was not affected by fasting, but fell in response to the clamp. 5. Fasting caused a progressive resistance to the effects of insulin and glucose on oxidative glucose disposal and on forearm glucose uptake. Insulin-mediated glucose storage was unaffected by fasting, but the apparent cost of this storage was reduced by fasting.
